tbuckley/cabot-search huggingface dataset:
Abstract 3939: Preclinical development of embryonic ectoderm development (EED) inhibitor APG-5918/EEDi-5273 for cancer therapy
Authors: Saijie Zhu, Douglas D. Fang, Qiang Li, Dongmei Yang, Shoulai Gu, Shaomeng Wang, Dajun Yang, Yifan Zhai
Journal: Cancer Research (2022)

Abstract Three core components constitute the polycomb repressive complex 2 (PRC2), a multiprotein complex that catalyzes methylation of histone H3 at lysine 27 (H3K27): (1) enhancer of zeste homolog 2 (EZH2), (2) EED, and (3) suppressor of zeste 12 protein homolog (SUZ12). Dysregulated function of PRC2 is implicated in the development of various cancer types. With regulatory approval of EZH2 inhibitor tazemetostat, a potentially effective successful cancer therapeutic strategy is now available for patients with epitheloid sarcoma and relapsed or refractory follicular lymphoma. However, EZH2 inhibitor activity might be reduced because of acquired resistance through secondary mutations in EZH2 or its inability to inhibit paralogs of EZH2 (including EZH1). Because binding of EED with trimethylated H3K27 (H3K27me3) is required to activate methyltransferase activity of EZH2, allosterically targeting EED is emerging as a novel approach to inhibit PRC2 (Qi et al, Nat Chem Biol 2017). APG-5918/EEDi-5273 is a well-documented, investigational, novel, bioactive, and potent EED inhibitor (Rej et al, JMC 2021). The aim of this study was to further characterize the anticancer therapeutic activity of APG-5918 in the preclinical setting. APG-5918/EEDi-5273 showed high-affinity binding to EED protein in a biochemical assay (IC50 = 1.2 nM). It also exerted potent antiproliferative activity in several EZH2 mutant (EZH2mut) diffuse large B-cell lymphoma (DLBCL) cell lines, with IC50 values in the nanomolar range and inhibitory effects that were approximately 5 times lower than those with tazemetostat. In a mouse xenograft model derived from EZH2mut KARPAS-422 DLBCL cells, single-agent APG-5918 conferred potent and dose-dependent antitumor activity, resulting in durable complete tumor regression that correlated with inhibition of H3K27me3, induction of PRC2 target genes, and drug exposure in tumors. In summary, our results provide scientific rationale for the clinical development of APG-5918/EEDi-5273 in EZH2mut lymphomas and, potentially, other hematologic malignancies and solid tumors. Citation Format: Saijie Zhu, Douglas D. Fang, Qiang Li, Dongmei Yang, Shoulai Gu, Shaomeng Wang, Dajun Yang, Yifan Zhai. Preclinical development of embryonic ectoderm development (EED) inhibitor APG-5918/EEDi-5273 for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3939.
Abstract 3531: Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression
Authors: Bin-Jin Hwang, Li-Chung Tsao, Chaitanya Acharya, Timothy Trotter, Pankaj Agarwal, Tao Wang, Junping Wei, Xiao-Yi Yang, Gang-jun Lei, Takuya Osada, Herbert Kim Lyerly, Michael A. Morse, Zachary Hartman
Journal: Cancer Research (2022)

Abstract Background: The majority of colorectal carcinomas (CRCs) are insensitive to anti-PD-1/PD-L1 immune checkpoint inhibitor (ICI) antibodies. While there are many causes for ICI insensitivity, recent studies suggest that the suppression of innate immunity through a loss of innate immune adaptor expression could be a root cause of this insensitivity and an important factor in the evolution of tumor immunosuppression. Methods: We interrogated mitochondrial antiviral signaling gene (MAVS) expression through bioinformatics analyses of multiple datasets to validate its suppression in clinical samples. We then engineered MAVS expressing tumor cells and tested its ability to elicit innate and adaptive anti-tumor immunity using both in vitro and in vivo approaches, which we then confirmed using MAVS expressing viral vectors. Finally, we observed that MAVS stimulated PD-L1expression in different types of tumor cells and then assessed the combination of PD-L1 ICI antibodies with MAVS tumor expression in vivo. Results: MAVS was significantly downregulated in CRCs, but its re-expression could stimulate broad cellular interferon-related responses, in both murine and patient-derived CRCs. In vivo, local MAVS expression elicited significant anti-tumor responses in both immune-sensitive and insensitive CRC models, through the stimulation of an interferon responsive axis that elicited tumor antigen-specific adaptive immunity. Critically, we found that tumor-intrinsic MAVS expression triggered systemic adaptive immune responses that enabled abscopal CD8+ T cell cytotoxicity against distant CRCs. As MAVS also induced PD-L1 expression, we further found synergistic anti-tumor responses in combination with anti-PD-L1 ICIs. Conclusion: These data demonstrate that intratumoral MAVS expression results in local and systemic tumor antigen-specific T cell responses, which could be combined with PD-L1 ICI to permit effective anti-tumor immunotherapy in ICI resistant cancers. We are further exploring to overcome the ICI insensitivity of other types of solid tumor, with MAVS-delivery strategies other than viral vectors. Citation Format: Bin-Jin Hwang, Li-Chung Tsao, Chaitanya Acharya, Timothy Trotter, Pankaj Agarwal, Tao Wang, Junping Wei, Xiao-Yi Yang, Gang-jun Lei, Takuya Osada, Herbert Kim Lyerly, Michael A. Morse, Zachary Hartman. Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3531.
Abstract 2315: Synergic antitumoral activity of TTFields stimulation and Chloride Intracellular Channel 1 (CLIC1) inhibition in human glioblastoma primary culture
Authors: Michele Mazzanti, Stefania Castiglione, Matteo Ranucci, Gaetano Cannavale, Francesca Cianci, Ivan Verduci
Journal: Cancer Research (2022)

Abstract Glioblastoma relapse inevitably occurs in the majority of patients after surgery. Chemo- and radio- therapy are in most cases ineffective, while Tumor Treating Fields (TTFields) therapy delays average tumor recurrence by a few months. It is widely accepted that tumor reappearance is a result of the proliferation of residual glioblastoma stem cell (GSC) subpopulation, which escaped surgery. Long-term TTFields stimulation in in vitro experiments mimic glioblastoma cells recrudescence. After the first three days of TTFields exposure, cell growth is totally inhibited. However, in prolonged experiments, despite the chronic presence of TTFields stimulation, glioblastoma cells reestablish the ability to proliferate, even if at low rate. At the end of twelve days, exponentially growing cells show an increase of stemness markers, a drop of the membrane resistance with a related increase of membrane current, and an average depolarized membrane potential. Twelve days of TTFields treatment resulted in progressive increase in GSCs in the tumor cell population from 10% to more than 30%. Our long-term goal is to improve TTFields antitumoral activity by linking brain stimulation with a pharmacological strategy targeting GSC proliferation. The objective of our study is to test the therapeutic potential of combining TTFields exposure with the inhibition of the protein transmembrane Chloride Intracellular Channel 1 (tmCLIC1), which is crucial for GSCs proliferation. tmCLIC1 activity increases under oxidative stress conditions. Preliminary experiments using the INOVITRO-LIVE system showed a cytoplasmic oxidation increase under acute TTFields stimulation. tmCLIC1 impairment by ion channel specific antagonists affected the G1/S checkpoint and hence, tumor cell proliferation. Targeting synergically different glioblastoma cell cycle checkpoints, G2/M with TTFields stimulation and G1/S with tmCLIC1 inhibition, would include the vast majority of glioblastoma cell population. Combination TTFields exposure and tmCLIC1 ion channel inhibition could represent an efficacious step forward in the treatment of glioblastoma. Citation Format: Michele Mazzanti, Stefania Castiglione, Matteo Ranucci, Gaetano Cannavale, Francesca Cianci, Ivan Verduci. Synergic antitumoral activity of TTFields stimulation and Chloride Intracellular Channel 1 (CLIC1) inhibition in human glioblastoma primary culture [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2315.
Abstract 3907: A pheno-multiomic integration analysis of primary samples of acute myeloid leukemia reveals biomarkers of cytarabine resistance
Authors: Gilad Silberberg, Bandana Vishwakarama, Brandon Walling, Chelsea Riveley, Alessandra Audia, Marianna Zipeto, Ido Sloma, Amy Wesa, Michael Ritchie
Journal: Cancer Research (2022)

Abstract The overall survival of patients diagnosed with Acute Myeloid Leukemia (AML) remains low. While initial responses to therapy are favorable, the duration of response is short and overcoming therapeutic resistance has proven difficult. A better understanding of the tumor cell biology and resistance mechanisms may shed light onto novel therapeutic targets that improve long-term outcome. In this study, we performed an exhaustive analysis to include deep tumor phenotyping, drug sensitivity profiling and comprehensive omic characterization. These datasets were included in integrative pharmaco-phenotypic-multiomic analyses to identify targets and biomarkers associated with cellular phenotype and drug response. Our results reveal that the major cellular discriminant within the cellular phenotype is CD34 expression, which associates with a high PDK-mediated metabolic profile and cytarabine sensitivity. Tumors exhibiting cytarabine resistance associate with a CD34-negative cellular phenotype and molecular characteristics such as MYC copy number gain, and increased expression of SAMDH1, FBP1 and TYMP proteins. Citation Format: Gilad Silberberg, Bandana Vishwakarama, Brandon Walling, Chelsea Riveley, Alessandra Audia, Marianna Zipeto, Ido Sloma, Amy Wesa, Michael Ritchie. A pheno-multiomic integration analysis of primary samples of acute myeloid leukemia reveals biomarkers of cytarabine resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3907.
Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study
Authors: Xianyong Yin, Kwangwoo Kim, Hiroyuki Suetsugu, So-Young Bang, Leilei Wen, Masaru Koido, Eunji Ha, Lu Liu, Yuma Sakamoto, Sungsin Jo, Rui-Xue Leng, Nao Otomo, Young-Chang Kwon, Yujun Sheng, Nobuhiko Sugano, Mi Yeong Hwang, Weiran Li, Masaya Mukai, Kyungheon Yoon, Minglong Cai, Kazuyoshi Ishigaki, Won Tae Chung, He Huang, Daisuke Takahashi, Shin-Seok Lee, Mengwei Wang, Kohei Karino, Seung-Cheol Shim, Xiaodong Zheng, Tomoya Miyamura, Young Mo Kang, Dongqing Ye, Junichi Nakamura, Chang-Hee Suh, Yuanjia Tang, Goro Motomura, Yong-Beom Park, Huihua Ding, Takeshi Kuroda, Jung-Yoon Choe, Chengxu Li, Hiroaki Niiro, Youngho Park, Changbing Shen, Takeshi Miyamoto, Ga-Young Ahn, Wenmin Fei, Tsutomu Takeuchi, Jung-Min Shin, Keke Li, Yasushi Kawaguchi, Yeon-Kyung Lee, Yong-Fei Wang, Koichi Amano, Dae Jin Park, Wanling Yang, Yoshifumi Tada, Yu Lung Lau, Ken Yamaji, Zhengwei Zhu, Masato Shimizu, Takashi Atsumi, Akari Suzuki, Takayuki Sumida, Yukinori Okada, Koichi Matsuda, Keitaro Matsuo, Yuta Kochi, Kazuhiko Yamamoto, Koichiro Ohmura, Tae-Hwan Kim, Sen Yang, Takuaki Yamamoto, Bong-Jo Kim, Nan Shen, Shiro Ikegawa, Hye-Soon Lee, Xuejun Zhang, Chikashi Terao, Yong Cui, Sang-Cheol Bae
Journal: Annals of the Rheumatic Diseases (2022)

Genome-wide association studies (GWAS) have identified >100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We aimed to prioritise genes underlying the 110 SLE loci that were identified in the latest East Asian GWAS meta-analysis.
Abstract 5195: Humanized CD3E,D,G mice: An ideal model for efficacy study of CD3-bispecific antibodies
Authors: xiaoliu Yang, cunxiang Ju, mingkun zhang, jing zhao
Journal: Cancer Research (2022)

Abstract CD3-targeting bispecific antibodies (CD3 bsAb) are designed to simultaneously bind to T cells and tumor cell antigens, leading to T-cell activation, proliferation, and tumor cell death. To create a better animal model for studies of CD3-TCBs, we developed the BALBc-hCD3EDG model by gene editing technology, Briefly, a large human genomic fragment containing CD3E,CD3D,CD3G as well as regulatory elements was introduced into the BALBc mouse genome and animals carrying human CD3E,D,G integration were selected to establish the new strain. The BALBc-hCD3EDG mice have a normal immune system and successfully express human CD3E,CD3D,CD3G on the T cell surface. As expected, cytotoxicity of activity T cells by redirecting with CD3-CD20 bsAb was observed in in vitro T cell-mediated killing assays using an A20 cell expressing human CD20. Furthermore, the growth of subcutaneously engrafted CT26 and hCD20-A20 tumors in BALBc-hCD3EDG mice, was strongly inhibited by CD3-TCB antibody treatment. In conclusion, the CD3EDG humanized mice are ideal models for preclinical studies of bispecific antibodies and other immunotherapies. Citation Format: xiaoliu Yang, cunxiang Ju, mingkun zhang, jing zhao. Humanized CD3E,D,G mice: An ideal model for efficacy study of CD3-bispecific antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5195.
Abstract 2890: The development of an Adaptable Drug Affinity Conjugate (ADAC) targeting CD40 for a flexible therapeutic peptide cargo delivery to dendritic cells
Authors: Ida Laurén, Mohamed Eltahir, Aman Mebrahtu, Rosanne Veerman, Juan Astorga, Aljona Saleh, Jimmy Ytterberg, Annika Lindqvist, Leif Dahllund, Anders Olsson, Oskar Andersson, Johan Rockberg, Helena Persson, Sara Mangsbo
Journal: Cancer Research (2022)

Abstract CD40 agonistic antibodies targeting antigen-presenting cells rely on simultaneous antigen presentation for optimal efficacy, as the co-stimulatory signal alone will not lead to T cell activation. Herein we have developed a novel Adaptable Drug Affinity Conjugate (ADAC), a refinement of a traditional Antibody Drug Conjugate (ADC) with a focus on tailored drug design. The cargo for ADAC is synthetic long peptides that can be modified with the profiled genetic data for each patient. The ADAC technology relies on a high-affinity interaction between a short non-immunogenic peptide-tag (pTag) and a single-chain fragment (scFv) and the targeting of CD40 expressing antigen-presenting cells. As a proof-of-concept study, we have generated data supporting a ~20 times improved half-life of peptide therapeutics bound up by the ADAC technology (in vitro), translating to improved peptide half-life in vivo along with a superior expansion of T cells in vitro and in vivo, compared to peptide and antibody mixed but not interacting physically. Through phage-display selection screening of novel CD40 agonistic antibodies, we identified a unique clone (STRIKE-1001). STRIKE-1001 binds a defined structural epitope (HDX-MS) of CD40 in a low nM range and is agonistic in an IgG2 format. Similar to selicrelumab, STRIKE-1001 does not block CD40L binding to Fc-CD40. STRIKE-1001 shows a dose-dependent agonistic activity (EC50 of ~28 nM based on measured induction of HLA-DR expression) on human DCs and can be designed into a bispecific antibody without loss of agonistic activity. STRIKE-1001 is currently incorporated into the ADAC platform to be used as the first-in-class candidate for flexible peptide cargo delivery ensuring T cell priming and expansion in vivo as a means to transform CD40 agonistic antibody to clinically relevant drug candidates. Citation Format: Ida Laurén, Mohamed Eltahir, Aman Mebrahtu, Rosanne Veerman, Juan Astorga, Aljona Saleh, Jimmy Ytterberg, Annika Lindqvist, Leif Dahllund, Anders Olsson, Oskar Andersson, Johan Rockberg, Helena Persson, Sara Mangsbo. The development of an Adaptable Drug Affinity Conjugate (ADAC) targeting CD40 for a flexible therapeutic peptide cargo delivery to dendritic cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2890.
Abstract 5996: Single tube PCR-based NGS assay for detection of multiple gene fusions from cell free total nucleic acid
Authors: Tejashree Modak, Jilong Li, Sean Polvino, Yue Ke, Zhaohui Wang, Alex V. Kotlar
Journal: Cancer Research (2022)

Abstract Introduction: Recently, liquid biopsy has begun to be adopted for treatment selection and drug-resistance assessment for cancers. However, currently liquid biopsy is mostly focused on analyzing cell-free DNA (cfDNA). Though analyzing RNA provides more accurate analysis for functional gene fusions, little is known about the stability and availability of cfRNA (cell free RNA). Here we report our one-tube robust cfTNA (cell free total nucleic acids) assay to analyze ctDNA and ctRNA simultaneously. Methods: We assessed Pillar’s cell free TNA panel performance on 2 confirmed fusion positive and 5 fusion negative samples that were serially diluted to obtain a total of 88 samples including replicates. An input of 10ng cfTNA was used for fusion positive samples with fusion frequency ranging from 0.2% to 20%. A range of 5 to 30ng input was used for fusion negative samples. The amount of input cfRNA was estimated as equal to the cfDNA input. Total nucleic acids were extracted and cfRNA was reverse transcribed. Amplicons targeted the specific breakpoints of 36 known fusion transcripts. Fusion positive samples were diluted for library prep to achieve fusion frequency of 0.5%, 1%, 4%, 5% and 20%. Novaseq was used for sequencing with an average depth of 200,000X and downsampled by 25%. Pillar Variant Analysis Toolkit (PiVAT®) was used to map and call fusions. Results: Among dilutions of &amp;gt;=4%, PiVAT achieved &amp;gt;=99% sensitivity and &amp;gt;=99.9% specificity in calling RNA fusions from 10ng input. Even at extremely low dilutions of &amp;lt;=1%, PiVAT achieved &amp;gt;= 50% sensitivity. Conclusion: Pillar’s cell free TNA panel offers a simple, rapid, and reliable workflow that enables detection of a broad range of clinically relevant gene fusions. Detection of fusion events in cell-free samples from noninvasive liquid biopsies represents an important step forward in cancer diagnosis and monitoring. Citation Format: Tejashree Modak, Jilong Li, Sean Polvino, Yue Ke, Zhaohui Wang, Alex V. Kotlar. Single tube PCR-based NGS assay for detection of multiple gene fusions from cell free total nucleic acid [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5996.
Escape from cell-cell and cell-matrix adhesion dependence underscores disease progression in gastric cancer organoid models
Authors: Yin Tong, Priscilla S W Cheng, Chung Sze Or, Sarah S K Yue, Hoi Cheong Siu, Siu Lun Ho, Simon Y K Law, Wai Yin Tsui, Dessy Chan, Stephanie Ma, Siu Po Lee, Annie S Y Chan, April S Chan, Shui Wa Yun, Ho Sang Hui, Siu Tsan Yuen, Suet Yi Leung, Helen H N Yan
Journal: Gut (2022)

Objective Cell-cell (CC) and cell-matrix (CM) adhesions are essential for epithelial cell survival, yet dissociation-induced apoptosis is frequently circumvented in malignant cells. Design We explored CC and CM dependence in 58 gastric cancer (GC) organoids by withdrawing either ROCK inhibitor, matrix or both to evaluate their tumorigenic potential in terms of apoptosis resistance, correlation with oncogenic driver mutations and clinical behaviour. We performed mechanistic studies to determine the role of diffuse-type GC drivers: ARHGAP fusions, RHOA and CDH1, in modulating CC (CCi) or CM (CMi) adhesion independence. Results 97% of the tumour organoids were CMi, 66% were CCi and 52% were resistant to double withdrawal (CCi/CMi), while normal organoids were neither CMi nor CCi. Clinically, the CCi/CMi phenotype was associated with an infiltrative tumour edge and advanced tumour stage. Moreover, the CCi/CMi transcriptome signature was associated with poor patient survival when applied to three public GC datasets. CCi/CMi and CCi phenotypes were enriched in diffuse-type GC organoids, especially in those with oncogenic driver perturbation of RHO signalling via RHOA mutation or ARHGAP fusions. Inducible knockout of ARHGAP fusions in CCi/CMi tumour organoids led to resensitisation to CC/CM dissociation-induced apoptosis, upregulation of focal adhesion and tight junction genes, partial reversion to a more normal cystic phenotype and inhibited xenograft formation. Normal gastric organoids engineered with CDH1 or RHOA mutations became CMi or CCi, respectively. Conclusions The CCi/CMi phenotype has a critical role in malignant transformation and tumour progression, offering new mechanistic information on RHO-ROCK pathway inhibition that contributes to GC pathogenicity.
Abstract 5412: Role of her3 mutations on breast cancer oncogenesis
Authors: Rosalin Mishra, Mary Kate Kilroy, Hima Patel, Samar Alanazi, Joan T. Garrett
Journal: Cancer Research (2022)

Abstract We sought to determine if naturally occurring mutations in HER3 could drive oncogenic growth of HER3KO HER2+ HCC1569 cells in which endogenous HER3 has been eliminated via CRISPR-Cas9. A series of HER3 mutations identified in breast cancer patients (F94L, V104L, G284R, D297Y, T355I, and E928G) were introduced using lentiviral transduction and stable cell lines were generated in HER3KOHCC1569 cells via puromycin selection. We identified HER3V104L mutation to have higher cell proliferation and higher p-HER3 expression compared to wild-type (wt) and empty-vector (EV) HER3. We observed that HCC1569HER3KO cells stably expressing WT and V104L were sensitive to increasing doses of neratinib (0.1-0.5 µM) concentration. Next we analyzed if this mutation rendered resistance to the recently FDA- approved irreversible HER2 tyrosine kinase inhibitor, tucatinib. Our data indicated that both that V104L cells were sensitive to higher concentration of tucatinib compared to neratinib. In parallel experiments, we utilized COS7 cells to examine the signaling properties of HER3V104L. Our data indicated that transient transfection of COS7 cells with HER3V104L mutant significantly induces p-HER3/p-AKT and p-HER2 expression compared to WT HER3 in a ligand dependent manner. In addition, we observed that the V104L mutation stabilizes HER3 protein expression independent of HER2 and ligand stimulation. Experiments are ongoing to determine whether V104L induced HER3 stabilization and downstream signaling activation is dependent on HER3 binding partners including EGFR, HER2 or HER4. We also aim to understand how the V104L mutation stabilizes HER3 expression. Structural modeling of V104L mutation will provide insight about the mechanism of stabilization of the HER3 protein. We will use MCF10A and HEK293 cells to determine the effect of the V104L mutation on HER3 expression and downstream signaling. We also aim to decipher the signaling mechanism that drives the oncogenic potential of V104L mutation. In addition, we are using various PDXs with different HER3 mutations to determine other driver HER3 mutations in breast cancer and how this can be targeted in the clinic using HER targeted therapy. Citation Format: Rosalin Mishra, Mary Kate Kilroy, Hima Patel, Samar Alanazi, Joan T. Garrett. Role of her3 mutations on breast cancer oncogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5412.